Antifungal compounds

ABSTRACT

The technical field of the invention is in pharmaceutical compounds and methods. In an aspect, the disclosure provides macrolide compounds suitable for use as antifungal agents, as well as methods for their use and compositions containing the same.

This application is a continuation of U.S. patent application Ser. No.15/968,692, filed May 1, 2018, allowed as U.S. Pat. No. 10,568,872,which is a continuation of U.S. patent application Ser. No. 15/207,384,filed Jul. 11, 2016, allowed as U.S. Pat. No. 9,956,207, which is a 371National Entry of PCT/US2015/011247, filed Jan. 13, 2015, which claimspriority to U.S. Provisional Patent Application No. 61/926,413, filedJan. 13, 2014, the contents of which are incorporated by reference intheir entireties.

BACKGROUND

Tacrolimus (also referred to as FK-506) is a compound known to haveimmunosuppressive activity. As an immunosuppressive, it is used in avariety of situations such as organ transplantations and eczematreatment. The structure of tacrolimus includes a macrocyclic lactone,and various structurally related macrolide compounds are known.

Relevant art: US 2006/0035918; U.S. Pat. No. 5,457,111.

SUMMARY OF THE INVENTION

In an aspect is a method for treating a patient suffering from a fungalinfection, the method comprising administering to the patient aneffective amount of a composition comprising a compound of formula (I)

In formula (I), “a” is a double bond optionally present (provided thatR⁵ or R^(5a) is not present); R¹ is selected from alkyl, alkenyl, or istaken together with R³ or R^(3a) to form a cycle; R³ and R^(3a) areindependently selected from —H and —OH, or R³ and R^(3a) together form═X, where X is selected from O, C, and N such that ═X and the carbonatom to which it is attached forms a carbonyl, oxime, substituted oxime,imine, substituted imine, hydrazone, substituted hydrazone, terminalolefin, or substituted olefin functional group, or wherein one of R³ andR^(3a) is taken together with R¹ or R⁵ or R^(5a) to form a cycle (andthe other is H); R⁵ and R^(5a) are independently selected from —H, —OH,or -OTBS, or R⁵ and R^(5a) together form ═O, or one of R⁵ and R^(5a) is—H and the other is taken together with R³ or R^(3a) to form a cycle; R⁷and R^(7a) are independently selected from —H, —OH, —NH₂, alkoxy,alkylcarboxy, alkenylcarboxy, and substituted versions thereof, or R⁷and R^(7a) together form ═Y, where Y is selected from O, and N such that═Y and the carbon atom to which it is attached forms a carbonyl or oximefunctional group; and R9 is selected from —H and —OH.

In embodiments:

the compound has the structure of formula (IA-a), (IA-b), or (IA-c)

the compound has the structure of formula (IB-a), (IB-b), (IB-c), or(IB-d)

wherein ═X is selected from ═C(R^(3b))(R^(3c)), ═N—OR^(3d),═N—NH(R^(3c)), and ═N—N═C(CH₃)₂, R^(3b) and R^(3c) are independentlyselected from —H, —CN, and unsubstituted alkyl, R^(3d) is selected fromH, alkyl, aralkyl, and a function group, and R^(3e) is alkyl;

the compound has the structure of formula (IC-a), (IC-b), (IC-c), or(IC-d)

the compound has the structure of formula (ID) or (IE)

and

the compound has the structure of formula (IF), (IG), or (IH)

In an aspect is an anti-fungal formulation comprising an effectiveamount of a compound having the structure of formula (I) as describedabove, and further comprising a second antifungal agent.

In an embodiment, the second antifungal agent is selected from compoundsaccording to formula (I), polyenes, imidazoles, triazoles, thiazoles,allylamines, and echinochandins.

In an embodiment, there is provided a compound according to any of thestructures described herein.

These and other aspects of the invention will be apparent to the skilledartisan based on the disclosure herein. The technical field of theinvention is in pharmaceutical compounds and methods.

DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS

The term “alkyl” as used herein refers to a branched, unbranched orcyclic saturated hydrocarbon group of 1 to about 50 carbon atoms, suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.Preferred alkyl groups herein may contain 1 to about 36, more typically1 to 10, carbon atoms. The alkyl groups described herein may beunsubstituted or they may be substituted with one or more substituentsincluding functional groups (e.g., amine, hydroxyl, an olefinic groupsuch as a vinyl or an allyl group), or the like. “Substituted alkyl”refers to alkyl substituted with one or more substituent groups, andthis includes instances wherein two hydrogen atoms from the same carbonatom in an alkyl are replaced, such as in a carbonyl group (i.e., asubstituted alkyl group may include a —C(═O)-moiety). Other substituentsinclude halogen, ether, hydroxyl, amine functional groups, etc. asdefined in more detail below (see “functional groups”). The terms“heteroatom-containing alkyl” and “heteroalkyl” refer to an alkylsubstituent in which at least one carbon atom is replaced with aheteroatom, such as o, S, P, or N, as described in further detail infra.If not otherwise indicated, the term “alkyl” includes linear, branched,cyclic, unsubstituted, substituted, heteroatom-containing, andsubstituted heteroatom-containing alkyl.

The term “alkylene” as used herein refers to a difunctional saturatedbranched or unbranched hydrocarbon chain containing from 1 to 50 carbonatoms, more typically from 1 to 12 carbon atoms, and includes, forexample, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), 2-methylpropylene (—CH₂—CH(CH₃)—CH₂—), hexylene(—(CH₂)₆—) and the like. Similarly, the terms “alkenylene,”“alkynylene,” “arylene,” “alkarylene,” and “aralkylene” refer todifunctional (i.e., linking) alkenyl, alkynyl, aryl, alkaryl, andaralkyl groups, respectively.

The term “alkenyl” as used herein refers to a linear, branched or cyclichydrocarbon group of 2 to about 50 carbon atoms containing at least onedouble bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl,isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl,tetracosenyl, and the like. Generally, although again not necessarily,alkenyl groups herein may contain 2 to about 36 carbon atoms, and forexample may contain 2 to 12 carbon atoms, or more typically 2 to 6carbon atoms. The term “substituted alkenyl” refers to alkenylsubstituted with one or more substituent groups, and the terms“heteroatom-containing alkenyl” and “heteroalkenyl” refer to alkenyl inwhich at least one carbon atom is replaced with a heteroatom. If nototherwise indicated, the term “alkenyl” includes linear, branched,cyclic, unsubstituted, substituted, heteroatom-containing, andsubstituted heteroatom containing alkenyl.

The term “alkynyl” as used herein refers to a linear or branchedhydrocarbon group of 2 to 50 carbon atoms containing at least one triplebond, such as ethynyl, n-propynyl, and the like. Generally, althoughagain not necessarily, alkynyl groups herein may contain 2 to about 18carbon atoms, and such groups may further contain 2 to 12 carbon atoms,or more typically 2 to 6 carbon atoms. The term “substituted alkynyl”refers to alkynyl substituted with one or more substituent groups, andthe terms “heteroatom-containing alkynyl” and “heteroalkynyl” refer toalkynyl in which at least one carbon atom is replaced with a heteroatom.If not otherwise indicated, the term “alkynyl” includes linear,branched, unsubstituted, substituted, and/or heteroatom-containingalkynyl.

The term “aryl” as used herein refers to an aromatic species having 1 to3 rings, but typically intends a monocyclic or bicyclic moiety, e.g.,phenyl or 1- or 2-naphthyl groups. Optionally, these groups aresubstituted with 1 to 4, more preferably 1 to 2, substituents such asthose described herein, including alkyl, alkoxy, hydroxyl, amino, and/ornitro. Aryl groups may, for example, contain 6 to 50 carbon atoms, andas a further example, aryl groups may contain 6 to 12 carbon atoms. Forexample, aryl groups may contain one aromatic ring or two fused orlinked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether,diphenylamine, benzophenone, and the like. “Substituted aryl” refers toan aryl moiety substituted with one or more substituent groups, and theterms “heteroatom-containing aryl” and “heteroaryl” refer to arylsubstituent, in which at least one carbon atom is replaced with aheteroatom. If not otherwise indicated, the term “aryl” includesunsubstituted, substituted, heteroatom-containing, and substitutedheteroatom-containing aromatic substituents.

The term “aralkyl” refers to an alkyl group with an aryl substituent,and the term “alkaryl” refers to an aryl group with an alkylsubstituent, wherein “alkyl” and “aryl” are as defined above. Ingeneral, aralkyl and alkaryl groups herein contain 6 to 50 carbon atoms.Aralkyl and alkaryl groups may, for example, contain 6 to 20 carbonatoms, and as a further example, such groups may contain 6 to 12 carbonatoms. Unless specified otherwise, the terms “alkaryl” and “aralkyl”include substituted, heteroatom-containing, and substitutedheteroatom-containing versions thereof.

The term “amino” intends an amino group —NR₂ where R is hydrogen or analternative substituent, typically alkyl. The term “amino” is thusintended to include primary amino (i.e., NH₂), “alkylamino” (i.e., asecondary amino group containing a single alkyl substituent), and“dialkylamino” (i.e., tertiary amino group containing two alkylsubstituents).

The term “heteroatom-containing” as in a “heteroatom-containing alkylgroup” (also termed a “heteroalkyl” group) or a “heteroatom-containingaryl group” (also termed a “heteroaryl” group) refers to a molecule,linkage or substituent in which one or more carbon atoms are replacedwith an atom other than carbon, e.g., nitrogen, oxygen, sulfur,phosphorus or silicon, typically nitrogen, oxygen or sulfur. Similarly,the term “heteroalkyl” refers to an alkyl substituent that isheteroatom-containing, the term “heterocyclic” refers to a cyclicsubstituent that is heteroatom-containing, the terms “heteroaryl” andheteroaromatic” respectively refer to “aryl” and “aromatic” substituentsthat are heteroatom-containing, and the like. Examples of heteroalkylgroups include alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylatedamino alkyl, and the like. Examples of heteroaryl substituents includepyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, furyl,pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc., and examplesof heteroatom-containing alicyclic groups are pyrrolidino, morpholino,piperazino, piperidino, tetrahydrofuranyl, etc.

“Halo” or “halogen” refers to fluoro, chloro, bromo or iodo, and usuallyrelates to halo substitution for a hydrogen atom in an organic compound.

By “substituted” as in “substituted hydrocarbyl,” “substituted alkyl,”“substituted aryl,” and the like, as alluded to in some of theaforementioned definitions, is meant that in the hydrocarbyl, alkyl,aryl, or other moiety, at least one hydrogen atom bound to a carbon (orother) atom is replaced with one or more non-hydrogen substituents.Examples of such substituents include, without limitation: C₁-C₂₄ alkyl(including C₁-C₁₈ alkyl, further including C₁-C₁₂ alkyl, and furtherincluding C₁-C₆ alkyl), C₂-C₂₄ alkenyl (including C₂-C₁₈ alkenyl,further including C₂-C₁₂ alkenyl, and further including C₂-C₆ alkenyl),C₂-C₂₄ alkynyl (including C₂-C₁₈ alkynyl, further including C₂-C₁₂alkynyl, and further including C₂-C₆ alkynyl), C₅-C₃₀ aryl (includingC₅-C₂₀ aryl, and further including C₅-C₁₂ aryl), C₆-C₃₀ aralkyl(including C₆-C₂₀ aralkyl, and further including C₆-C₁₂ aralkyl), C₆-C₃₀alkaryl (including C₆-C₂₀ alkaryl, and further including C₆-C₁₂alkaryl), and functional groups such as halo, hydroxyl, sulfhydryl,C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₀ aryloxy,acyl (including C₂-C₂₄ alkylcarbonyl (—CO-alkyl) and C₆-C₂₀ arylcarbonyl(—CO-aryl)), acyloxy (—O-acyl), C₂-C₂₄ alkoxycarbonyl (—(CO)—O-alkyl),C₆-C₂₀ aryloxycarbonyl (—(CO)—O-aryl), halocarbonyl (—CO)-X where X ishalo), C₂-C₂₄ alkylcarbonato (—O—(CO)—O-alkyl), C₆-C₂₀ arylcarbonato(—O—(CO)—O-aryl), C₂-C₂₄ alkylcarbonyloxy (—O-(CO)-alkyl), C₆-C₂₄arylcarbonyloxy (—O—(CO)-aryl), carboxy (—COOH), carboxylato (—COO—),carbamoyl (—(CO)—NH₂), mono-substituted C₁-C₂₄ alkylcarbamoyl(—(CO)—NH(C₁-C₂₄ alkyl)), di-substituted alkylcarbamoyl (—(CO)—N(C₁-C₂₄alkyl)₂), mono-substituted arylcarbamoyl (—(CO)—NH-aryl), thiocarbamoyl(—(CS)—NH₂), carbamido (—NH—(CO)—NH₂), cyano (—C≡N), isocyano (—N+≡C—),cyanato (—O—C≡N), isocyanato (—O—N≡C—), isothiocyanato (—S—C≡N), azido(—N═N+═N—), formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH₂), mono-and di-(C₁-C₂₄ alkyl)-substituted amino, mono- and di-(C₅-C₂₀aryl)-substituted amino, C₂-C₂₄ alkylamido (—NH—(CO)-alkyl), C₅-C₂₀arylamido (—NH—(CO)-aryl), imino (—CR═NH where R=hydrogen, C₁-C₂₄ alkyl,C₅-C₂₀ aryl, C₆-C₂₀ alkaryl, C₆-C₂₀ aralkyl, etc.), alkylimino(—CR═N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), arylimino(—CR═N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro(—NO₂), nitroso (—NO), sulfo (—SO₂—OH), sulfonato (—SO₂—O—), C₁-C₂₄alkylsulfanyl (—S-alkyl; also termed “alkylthio”), arylsulfanyl(—S-aryl; also termed “arylthio”), C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl),C₅-C₂₀ arylsulfinyl (—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl),C₅-C₂₀ arylsulfonyl (—SO₂-aryl), phosphono (—P(O)(OH)₂), phosphonato(—P(O)(O—)₂), phosphinato (—P(O)(O—)), phospho (—PO₂), phosphino (—PH₂),mono- and di-(C₁-C₂₄ alkyl)-substituted phosphino, and mono- anddi-(C₅-C₂₀ aryl)-substituted phosphino. In addition, the aforementionedfunctional groups may, if a particular group permits, be furthersubstituted with one or more additional functional groups or with one ormore hydrocarbon moieties (alkyl, aryl, etc.). Analogously, theabove-mentioned hydrocarbon moieties may be further substituted with oneor more functional groups or additional hydrocarbon moieties such asthose specifically enumerated. It will be appreciated that functionalgroups may be attached via a heteroatom or, where appropriate, via acarbon atom, to the remainder of the compound.

In an aspect is a compound having the structure of formula (I)

In formula (I), “a” is a double bond optionally present (provided thatR⁵ or R^(5a) is not present); R¹ is selected from alkyl, alkenyl, or istaken together with R³ or R^(3a) to form a cycle; R³ and R^(3a) areindependently selected from —H and —OH, or R³ and R^(3a) together form═X, where X is selected from O, C, and N such that ═X and the carbonatom to which it is attached forms a carbonyl, oxime, substituted oxime,imine, substituted imine, hydrazone, substituted hydrazone, terminalolefin, or substituted olefin functional group, or wherein one of R³ andR^(3a) is taken together with R¹ or R⁵ or R^(5a) to form a cycle (andthe other is H); R⁵ and R^(5a) are independently selected from —H, —OH,or -OTBS, or R⁵ and R^(5a) together form ═O, or one of R⁵ and R^(5a) is—H and the other is taken together with R³ or R^(3a) to form a cycle; R⁷and R^(7a) are independently selected from —H, —OH, —NH₂, alkoxy,alkylcarboxy, alkenylcarboxy, and substituted versions thereof, or R⁷and R^(7a) together form ═Y, where Y is selected from O, and N such that═Y and the carbon atom to which it is attached forms a carbonyl or oximefunctional group; and R9 is selected from —H and —OH.

In formula (I), R¹ is selected from alkyl and alkenyl, or R¹ may betaken together with R³ or R^(3a) to form a cycle. Examples of alkylgroups include methyl and substituted methyl (e.g., —C(═O)—Me,—C(═O)—OH, and —C(═O)—OMe), while examples of alkenyl groups include—CH═CR^(1c)R^(1d). Where R¹ is —CH═CR^(1c)R^(1d), the double bond may bein the E- or Z-configuration, and the formulation may comprise a singleisomer or a mixture of isomers. In embodiments, R¹ is unsubstitutedalkyl or unsubstituted alkenyl.

R^(1c) and R^(1d) are independently selected from: H, alkyl, aryl,alkaryl, aralkyl, and a functional group. Examples include —(CH₂)_(n)CH₃where n is an integer (e.g., an integer in the range 0-20, or an integerselected from 0, 1, 2, 3, 4, 5, etc.), cyclohexyl, substituted alkyl(substituents such as aryl and functional groups), phenyl, substitutedphenyl (substituents such as alkyl, alkenyl, functional groups, etc.),alkoxycarbonyl (e.g., C(═O)O-alkyl and C(═O)O-aryl), alkylsulfonyl(e.g., —SO₂—Me or —SO₂—Et), etc.

In embodiments, R¹ is alkyl including branched alkyl, such as methyl,ethyl, i-propyl, butyl, t-butyl, etc.

In any of the embodiments of formula (I) described herein where R¹ isnot part of a cycle, R¹ may be selected from —Me and —CH═CH₂.

In embodiments, R¹ is taken together with R³ or R^(3a) to formsubstituted or unsubstituted pyridazine.

In embodiments of formula (I), R³ and R^(3a) are independently selectedfrom —H or —OH, or R³ and R^(3a) are taken together to form ═X, where Xis O, N, or C such that X and the carbon atom to which it is attachedform carbonyl, oxime, substituted oxime, imine, substituted imine,hydrazone, or substituted hydrazone, or X is C to form an olefin(terminal or internal). In embodiments, ═X is selected from ═O,═C(R^(3b))(R^(3c)), ═N—OR^(3d), ═N—N═C(CH₃)₂, and ═N—NH—R^(3e), orwherein R³ or R^(3a) is taken together with R¹ or R⁵ or R^(5a) to form acycle. In embodiments, R³ and R^(3a) together are ═O;═C(R^(3b))(R^(3c)); or ═N—OR^(3d). In embodiments, R³ and R^(3a)together are ═O or ═C(R^(3b))(R^(3c)). In embodiments, R³ and R^(3a)together are ═N—OR^(3d), with two isomers present for the possibleorientations of the —OR^(3d) group. The compound may be racemic (withboth isomers) or may be a single oxime isomer in the formulationsdescribed herein.

In embodiments, R³ and R^(3a) are both H.

In embodiments, R^(3b) and R^(3c) are independently selected from H andunsubstituted alkyl. In embodiments R^(3b) and R^(3c) are both H. Inembodiments exactly one of R^(3b) and R^(3c) is H and the other isunsubstituted alkyl. In embodiments both R^(3b) and R^(3c) areunsubstituted alkyl. Examples of alkyl include methyl, ethyl, propyl(n-propyl or i-propyl), butyl (n-butyl, i-butyl, t-butyl), pentyl, andhexyl. In other embodiments, one of R^(3b) and R^(3c) is H, and theother is —CN.

R^(3d) is selected from H, alkyl, aralkyl, and a function group.Examples of alkyl include methyl, ethyl, propyl (i.e., n- and i-propyl),butyl (i.e., n-, i-, and t-butyl), —(CH₂)_(n)—CH₃ (wherein n is in therange 1-5 or 1-3, or is 1, 2, 3, 4, or 5), —CH₂—COOH, and —(CH₂)_(n)—OH(wherein n is in the range 1-5 or 2-4, or is 1, 2, 3, 4, or 5). Examplesof aralkyl include —CH₂—C₆H₄—NO₂ and —CH₂-C₆H₃Cl₂. Examples offunctional groups include —S(═O)₂—OH.

R^(3e) is alkyl. Examples of alkyl include methyl, ethyl, propyl (i.e.,n- and i-propyl), butyl (i.e., n-, i-, and t-butyl), —(CH₂)_(n)—CH₃(wherein n is in the range 1-5 or 1-3, or is 1, 2, 3, 4, or 5),—(CH₂)_(n)—OH (wherein n is in the range 1-5 or 2-4, or is 1, 2, 3, 4,or 5), etc.

In formula (I), in embodiments, bond “a” is present and R^(5a) is notpresent. In other embodiments, bond “a” is not present and R^(5a) ispresent. In some such embodiments, R^(5a) is H.

In formula (I), one of R⁵ and R^(5a) is —OH or -OTBS and the other is H,or R⁵ and R^(5a) taken together form ═O, or R⁵ is taken together with R³to form a cycle. In embodiments, R³ or R^(3a) and R⁵ or R^(5a) are takentogether to form a cycle such as a ketal or acetal (e.g., adimethylacetonide).

In formula (I), one of R⁷ and R^(7a) is selected from —OH, —NH₂,alkylcarboxy (e.g., —O—CO—CH₂—COOH), alkenylcarboxy (e.g.,—O—CO—CH₂CH₂CH═CH₂, —O—CO—CH₂CH₂CH═CH—COOH, etc.), and thiocarbonato(e.g., —O—C(═S)—O—R where R is alkyl or aryl). Alternatively, R⁷ andR^(7a) together form ═Y, where ═Y is N or O to form an oxime or carbonylgroup.

In embodiments, R⁷ and R^(7a) are both —H.

In embodiments, the compounds have the structure of formula (IA-a),(IA-b), or (IA-c)

In formula (IA-a), (IA-b), and (IA-c), one of R³ and R^(3a) is H and theother is taken with R¹ (formula IA-c) or with R⁵ or R^(5a) to form acycle; and R⁷, and R^(7a) are as defined for formula (I).

For example, in formula (IA-a) and (IA-b), R⁷ and R^(7a) are OH and H,respectively, R³ and R^(5a) are —H, and R^(3a) and R⁵ are taken togetherto form a cycle. An example cycle is an acetonide group. Alternatively,R³ and R⁵ are H, and R^(3a) and R^(5a) are taken together to form anacetonide or other cycle. Alternatively, R^(3a) and R⁵ are H, and R³ andR^(5a) are taken together to form an acetonide or other cycle.Alternatively, R^(3a) and R^(5a) are H, and R³ and R⁵ are taken togetherto form an acetonide or benzylidene acetal (i.e. —O—C(H)(Ph)—O- wherethe oxygen atoms are connected at C22 and C24). In such compounds, R⁷and R^(7a) may alternatively both be —H, or may together form ═O.

For example, in formula (IA-c), R⁷ and R^(7a) are OH and H,respectively, R⁵ and R^(5a) are OH and H, respectively, and R³ or R^(3a)is taken together with R¹ to form a substituted or unsubstitutedpyridazine cycle (the other of R³ and R^(3a) being H). Examplesubstituents are alkyl.

In embodiments, the compounds have the structure of formula (IB-a) or(IB-b) or (IB-c) or (IB-d):

In embodiments of formula (IB-a), (IB-b), (IB-c), and (IB-d), ═X isselected from ═C(R^(3b))(R^(3c)), ═N—OR^(3d), ═N—NH(R^(3e)), and═N—N═C(CH₃)₂, R^(3b), R^(3c), R^(3d), R^(3e), R⁵, R⁷, and R^(7a) are asdefined previously for formula (I).

For example, in formula (IB-a), (IB-b), (IB-c), and (IB-d), R⁵ is —OH,R⁷ and R^(7a) are OH and H, respectively, and X is ═CH₂.

For example, in formula (IB-a), (IB-b), (IB-c), and (IB-d), R⁵ is —OH,R⁷ and R^(7a) are OH and H, respectively, and X is ═N—OH.

For example, in formula (IB-a), (IB-b), (IB-c), and (IB-d), R⁵ is —OH,R⁷ and R^(7a) are OH and H, respectively, and X is ═N—O—R^(3d). Forexample, R⁵ is —OH, R⁷ and R^(7a) are OH and H, respectively, and X isselected from ═N—O—CH₃, ═N—O-(CH₂)_(n)-CH₃ (n=1, 2, or 3),═N—O—CH(CH₃)₂, ═N—O—C(CH₃)₃, ═N—O-(CH₂)_(n)—OH (n=1, 2, or 3), and═N—O-(CH₂)_(n)—COOH (n is 1, 2, or 3). Or for example, R⁵ is —OH, R⁷ andR^(7a) are OH and H, respectively, and X is ═N—O—CH₂-aryl, where aryl isphenyl, nitrophenyl (e.g., 4-nitrophenyl), or halophenyl (e.g.,chlorophenyl such as 4-chlorophenyl, dichlorophenyl such as2,4-dichlorophenyl, and trichlorophenyl such as 2,4,6-trichlorophenyl).

For example, in formula (IB-a), (IB-b), (IB-c), and (IB-d), R⁵ is —H or—OH, R⁷ and R^(7a) are OH and H, respectively, and X is ═C(H)(CN). Alsofor example, X is ═C(Me)(Et).

For example, in formula (IB-a), (IB-b), (IB-c), and (IB-d), R⁵ is —H or—OH, R⁷ and R^(7a) are OH and H, respectively, X is ═N—NH—R^(3e), andR^(3e) is selected from methyl, ethyl, i-propyl, n-propyl, and—(CH₂)_(n)—OH (n is 0, 1, 2, or 3).

For example, in formula (IB-a), (IB-b), (IB-c), and (IB-d), R⁵ is —H or—OH, R⁷ and R^(7a) are OH and H, respectively, X is ═N—N═C(CH₃)₂.

For example, in formula (IB-a), (IB-b), (IB-c), and (IB-d), R⁵ is —H or—OH, R⁷ and R^(7a) are OH and H, respectively, X is ═N—O—SO₂—H or═N—O—SO₂—R where R is alkyl such as Me.

For example, in formula (IB-a), (IB-b), (IB-c), and (IB-d), R⁵ is —H or—OH, R⁷ and R^(7a) are taken together to form ═N—OH, and X is ═N—OH.

For example, in formula (IB-a), (IB-b), (IB-c), and (IB-d), one of R⁷and R^(7a) is —H and the other is —OH, R⁵ is —H, —OH, or -OTBS, and X is═N—OH, ═N—OR^(3j), or ═N—NHMe, where R^(3j) is alkyl such as methyl,ethyl, propyl, butyl, etc.

In embodiments of formula (IB-a), (IB-b), (IB-c), and (IB-d), R⁷ andR^(7a) are —H, R⁵ is —H or —OH, and X is ═N—OH, ═N—OR^(3j), or ═N—NHMe,where R^(3j) is alkyl such as methyl, ethyl, propyl, butyl, etc.

In embodiments of formula (IB-a), (IB-b), (IB-c), and (IB-d), R⁵ is —Hor —OH, X is ═CH₂ or ═O, and R⁷ and R^(7a) together form ═O.

In embodiments of formula (IB-a), (IB-b), (IB-c), and (IB-d), R⁷ andR^(7a) are —OH and —H, respectively (or, they are both —H), R⁵ is —H or—OH, and X is ═C(R^(3b))(R^(3c)), where R^(3b) and R^(3c) areindependently selected from —H, —CN, and alkyl.

In each of the above oxime and alkene compounds for formula (IB-a),(IB-b), (IB-c), and (IB-d), the oxime/alkene may exist as a racemicmixture of two isomers, or may be present as a single isomer. Isolationof single isomers is generally within the skill in the art.

In embodiments of formula (IB-a), (IB-b), (IB-c), and (IB-d), R⁵ is —OHor —H, X is ═O and R⁷ and R^(7a) are both H.

In any of the foregoing embodiments of formula (IB-a), (IB-b), (IB-c),and (IB-d), R⁷ and R^(7a) may alternatively together form ═O, or mayalternatively both be —H.

In embodiments, the compounds have the structure of formula (IC-a),(IC-b), (IC-c), or (IC-d)

In Formula (IC-a), (IC-b), (IC-c), and (IC-d), R³, R^(3a), R⁷, andR^(7a) are as defined in Formula (I). In embodiments, R³ and R^(3a)together form ═O, one of R⁷ and R^(7a) is —H, and the other is selectedfrom —OH, alkoxy, alkylcarboxy, alkenylcarboxy, and substituted versionsthereof.

For example, in formula (IC-a), (IC-b), (IC-c), and (IC-d), R³ andR^(3a) together form ═O, R^(7a) is —H, and R⁷ is —OH or —O—C(═O)-R^(7c),where R^(7c) is —(CH₂)_(n)-COOH or —(CH₂)_(n)-CH═CHR^(7d) (n is 1, 2, or3), and R^(7d) is —H, alkyl (e.g., methyl, ethyl, etc), or —COOH.

For example, in formula (IC-a), (IC-b), (IC-c), and (IC-d), R^(7a) is—H, R⁷ is —OH and R³ and R^(3a) together form ═N—NH—R^(7e), ═N—OH, or═N—OR^(7e), where R^(7e) is alkyl (e.g., methyl or ethyl, etc.).

In embodiments, the compounds have the structure of formula (ID) or (IE)

In formula (ID) and (IE), R¹, R⁷, R^(7a), and R⁹ are as defined informula (I). The wavy line indicates that the hydroxyl substituent canbe either isomer, and both isomers are intended to be included.

In embodiments of formula (ID) and (IE), R¹ is alkyl or alkenyl, R^(7a)and R⁹ are —H, and R⁷ is selected from alkoxy, alkylcarboxy,alkenylcarboxy, and substituted versions thereof. For example, R¹ ismethyl, R^(7a) and R⁹ are —H, and R⁷ is —OC(═O)-(CH₂)_(n)-COOH (n is 1,2, or 3). For example, R¹ is —CH═CH₂, R^(7a) and R⁹ are —H, and R⁷ is—OC(═O)-(CH₂)_(n)-COOH (n is 1, 2, or 3). For example, R¹ is methyl,R^(7a) and R⁹ are —H, and R⁷ is —OH. For example, R¹ is —CH═CH₂, R^(7a)and R⁹ are —H, and R⁷ is —OH.

In embodiments of formula (ID) and (IE), R¹ is alkyl or alkenyl, R^(7a)is —H, and R⁷ and R⁹ are both hydroxyl. For example, R¹ is methyl. Forexample, R¹ is —CH═CH₂.

In embodiments the compounds have the structure of formula (IF-a) or(IF-b)

In formula (IF), R¹, R⁵, R⁷, and R^(7a) are as defined in formula (I).

In embodiments of formula (IF), R¹ is alkyl or alkenyl, R⁵ is —OH, R⁷ isH, and R^(7a) is amine. For example, R¹ is methyl, R⁵ is —OH, R⁷ is H,and R^(7a) is —NH₂. For example, R¹ is —CH═CH₂, R⁵ is —OH, R⁷ is H, andR^(7a) is —NH₂. For example, R¹ is methyl or —CH═CH₂, R⁵ is —OH, R^(7a)is H, and R⁷ is —NH₂.

In embodiments of formula (IF), R¹ is alkyl or alkenyl, R⁵ is -OTBS, R⁷is H, and R^(7a) is amine. For example, R¹ is methyl, R⁵ is -OTBS, R⁷ isH, and R^(7a) is —NH₂. For example, R¹ is —CH═CH₂, R⁵ is -OTBS, R⁷ is H,and R^(7a) is —NH₂. For example, R¹ is methyl or —CH═CH₂, R⁵ is -OTBS,R^(7a) is H, and R⁷ is —NH₂. Also for example, R¹ is methyl or —CH═CH₂,R⁵ is -OTBS, R^(7a) is H, and R⁷ is —H.

In embodiments of formula (IF), R¹ is alkyl or alkenyl, R⁵ is —OH, andR⁷ and R^(7a) are —H. For example, R¹ is methyl or —CH═CH₂, R⁵ is —OH,and R⁷ and R^(7a) are —H.

In embodiments of formula (IF), R¹ is alkyl or alkenyl, R⁵ is —OH, andR⁷ and R^(7a) are thiocarbonato and —H, respectively. For example, R¹ ismethyl or —CH═CH₂, R⁵ is —OH, R^(7a) is H, and R⁷ is —O—C(═S)-O-alkyl or—O-C(═S)-O-aryl. For example, R⁷ is —O-C(═S)-O-methyl or —O-C(═S)-O—Ph.

In embodiments of formula (IF), R⁵ is —OH, and R⁷ and R^(7a) togetherform ═O, and R¹ is selected from alkenyl. For example, R⁵ is —OH, and R⁷and R^(7a) together form ═O, and R¹ is —CH═CH-(CH₂)_(n)-R^(7f), where nis 1, 2, 3, 4, 5, or greater than 5, and R^(7f) is methyl, —OH, alkoxy,or aryloxy. For example, R⁵ is —OH, and R⁷ and R^(7a) together form ═O,and R¹ is selected from —CH═CH-(CH₂)_(n)—O—R^(7g), where n is 1, 2, 3,or 4, and R^(7g) is methyl, —OH, —OMe, or —OPh.

In embodiments of formula (IF), R⁵ is —OH, and R⁷ and R^(7a) are —OH and—H, respectively, and R¹ is selected from alkyl and alkenyl. Forexample, R¹ is methyl or —CH═CH₂.

In embodiments, the compounds have the structure of formula (IG)

In formula (IG), R¹, R⁷, and R^(7a) are as defined in formula (I).

For example, R¹ is selected from alkyl and alkenyl, one of R⁷ and R^(7a)is —H, and the other is selected from —H and —OH. For example, R⁷ is—OH, R^(7a) is —H, and R¹ is methyl, or —CH═CH₂. Also for example, R⁷and R^(7a) together form ═O, and R¹ is selected from alkyl and alkenyl(e.g., —Me, —CH═CH₂, etc.). Also for example, both R⁷ an R^(7a) are —H.

In embodiments, the compounds have the structure of formula (IH)

In formula (IH), R¹ is as defined in formula (I).

For example, R¹ is alkyl, including substituted methyl. For example, R¹is methyl, —C(═O)-Me, —C(═O)-OH or —CHR^(1a)R^(1b), wherein one ofR^(1a) and R^(1b) is —H and the other is selected from —H, carboxylicacid, and alkylcarbonyl such as —C(═O)Me or —C(═O)Et.

For example, R1 is alkenyl, including substituted alkenyl. Examplesinclude —CH═CH₂, —CH═CH(CH₃) (E and Z configuration), —CH═C(CH₃)₂, and—CH═CH(R^(1e)) wherein R^(1e) is alkyl. Examples of R^(1e) include—(CH₂)_(n)-R^(1f) (where n is in the range 1-20, or 1-10, and R^(1f) isMe or —OH), acetals, alkyl groups substituted with sufone andsulfonyloxy groups, alkyl groups substituted with ester or carbonyloxygroups, cyclic alkyl groups including heterocyclic alkyl groups, arylgroups including heterocyclic aryl groups, heteroatoms substituted withalkyl groups, ketone groups, amide groups, bicyclic groups includingbicyclic aromatic and bicyclic heteroatom-containing groups, and thelike.

Unless otherwise specified, reference to “formula (I)” includes allsub-formulae of formula (I) (i.e., IA-a, IA-b, IA-c, IB-a, IB-b, etc.).

Included are salts (e.g., pharmaceutically acceptable salts) of thecompounds of formula (I). Examples of salts are halo salts (e.g.,chloride, fluoride, bromide, or iodide salts), fluorinated salts such asperfluoroacetic acid (CF₃COOH) salt, acetic acid salt, and the like.

Examples of specific compounds according to formula (I) are given inTable 1.

In an aspect, the compounds are useful in treating a fungal infection ina patient. Patients include human patients as well as non-human patients(e.g., domesticated animals and the like).

In an aspect, a patient suffering from a fungal infection is treatedwith a formulation containing at least one compound according to aformula herein.

Examples of fungal infections suitable for treatment by formulationsdescribed herein include Candida, Aspergillus, Microsporum,Trichophyton, Cryptococcus, and Epidermophyton.

The compounds disclosed herein may be used as a pharmaceutically activecompound to prepare a pharmaceutically active formulation. Suchformulation may further comprise additives such as pharmaceuticallyacceptable carriers, colorants, flavorants, binders, etc., and mayfurther comprise coatings (if in solid dosage form), solvents (if inliquid oral, spray, or injectable form), and the like.

The total daily dose of the described compounds administered to apatient may range from about 0.001 to about 3 mg/kg/day. For purposes oforal administration, more preferable doses may be in the range of fromabout 0.005 to about 1.5 mg/kg/day. If desired, the effective daily dosemay be divided into multiple doses for purposes of administration;consequently, single dose compositions may contain such amounts orsubmultiples thereof to make up the daily dose.

In embodiments, the formulation comprises a second antifungal agent. Thesecond antifungal agent may be another compound according to theformulae herein. In embodiments, the second antifungal agent is a knownantifungal and not a compound according to the formulae herein, such asa polyene, imidazole, triazole, thiazole, allylamine, echinocandin,among others. Examples include Amphotericin B, Candicidin, Filipin,Hamycin, Natamycin, Nystatin, Rimocidin, Bifonazole, Butoconazole,Clotrimazole, econazole, fenticonazole, isoconazole, kentoconazole,miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole,tioconazole, albaconazole, fluconazole, isavuconazole, itraconazole,posaconazole, ravuconazole, terconazole, voriconazole, abafungin,amorolfin, butenafine, naftifine, terbinafine, anidulafungin,caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine,griseofulvin, haloprogin, polygodial, tolnaftate, undecylenic acid, andcrystal violet, among others.

TABLE 1 Antifungal Compounds 2

C₅₁H₇₃NO₁₄ 3

C₄₈H₇₇NO₁₂ 4

C₄₉H₇₉NO₁₂ 5

C₄₆H₇₁NO₁₄ 6

C₄₇H₇₃NO₁₄ 7

C₄₇H₇₃NO₁₄ 8

C₄₈H₇₅NO₁₄ 9

C₄₃H₇₆N₂O₁₂Si 10

C₄₃H₆₇NO₁₁ 11

C₄₉H₈₄N₂O₁₁Si 12

C₃₆H₅₉NO₁₁ 13

C₃₆H₅₉NO₁₁ 14

C₄₉H₇₇NO₁₄ 15

C₆₀H₁₀₁NO₁₂ 16

C₅₄H₈₉NO₁₂ 17

C₅₇H₉₅NO₁₂ 18

C₅₀H₇₉NO₁₂ 19

C₅₂H₇₅NO₁₄ 20

C₄₇H₇₅NO₁₂ 21

C₅₀H₈₁NO₁₂ 22

C₅₂H₈₅NO₁₂ 23

C₅₀H₇₉NO₁₂ 24

C₅₁H₈₁NO₁₂ 25

C₄₈H₇₂N₂O₁₂S 26

C₅₁H₇₃N₃O₁₂ 27

C₄₇H₇₀BrN₃O₁₂ 28

C₄₈H₇₅NO₁₃ 29

C₃₇H₆₂N₂O₁₂ 30

C₅₆H₈₄N₂O₁₃ 31

C₅₃H₈₅NO₁₄ 32

C₅₃H₈₅NO₁₄ 33

C₄₃H₇₁NO₁₁ 34

C₄₃H₇₁NO₁₁ 35

C₄₃H₇₂N₂O₁₀ 36

C₈₆H₁₃₄N₂O₂₄ 37

C₅₅H₈₉NO₁₄ 38

C₁₁H₂₀O₂ 39

C₄₈H₇₇NO₁₂ 40

C₄₉H₇₉NO₁₂ 41

C₄₉H₇₉NO₁₂ 42

C₄₄H₆₇NO₁₂ 43

C₄₃H₆₇NO₁₂ 44

C₄₃H₆₉NO₁₃ 45

C₄₃H₆₉NO₁₃ 46

C₄₃H₆₉NO₁₃ 47

C₄₅H₆₉NO₁₄ 48

C₄₈H₇₃NO₁₂ 49

C₄₉H₇₃NO₁₄ 50

C₄₇H₇₅NO₁₃ 51

C₅₄H₇₉NO₁₆ 52

C₅₅H₈₅NO₁₄ 53

C₄₉H₇₇NO₁₄ 54

C₄₆H₆₉NO₁₄ 55

C₄₇H₇₃NO₁₅ 56

C₄₉H₇₇NO₁₅ 57

C₅₁H₈₁NO₁₄ 58

C₄₆H₇₁NO₁₄ 59

C₄₆H₇₁NO₁₄ 60

C₄₆H₇₁NO₁₄ 61

C₄₅H₇₁NO₁₂ 62

C₄₆H₇₃NO₁₂ 63

C₄₉H₇₉NO₁₂ 64

C₄₇H₇₃NO₁₂ 65

C₄₈H₇₅NO₁₂ 66

C₄₉H₇₇NO₁₂ 67

C₄₅H₇₁NO₁₃ 68

C₄₇H₇₃NO₁₄ 69

C₄₆H₇₁NO₁₃ 70

C₄₆H₇₃NO₁₄S 71

C₅₁H₇₅NO₁₃ 72

C₅₁H₇₃NO₁₃ 73

C₄₃H₆₉NO₁₂ 74

C₄₇H₇₅NO₁₂ 75

C₄₇H₇₅NO₁₂ 76

C₄₆H₇₃NO₁₂ 77

C₄₈H₇₇NO₁₄ 78

C₄₆H₇₁NO₁₄ 79

C₄₉H₇₇NO₁₂ 80

C₅₁H₈₂N₂O₁₂ 81

C₄₆H₇₁NO₁₆ 82

C₅₀H₇₃NO₁₂ 83

C₄₄H₆₉NO₁₃ 84

C₄₈H₇₅NO₁₄ 85

C₄₄H₆₇NO₁₁ 86

C₄₄H₇₀N₂O₁₂ 87

C₄₄H₇₀N₂O₁₂ 88

C₄₅H₇₂N₂O₁₂ 89

C₄₅H₇₂N₂O₁₂ 90

C₄₉H₇₇NO₁₄ 91

C₄₉H₇₉NO₁₂ 92

C₁₈H₃₄O₂ 93

C₁₈H₃₄O₃ 94

C₁₈H₃₆O₃ 95

C₈H₁₆O₃ 96

C₄₇H₇₅NO₁₄ 97

C₅₄H₈₁NO₁₅S 98

C₄₇H₇₅N₃O₁₁ 99

C₄₆H₇₅N₃O₁₂ 100

C₄₄H₇₁NO₁₁ 101

C₄₆H₇₄N₂O₁₃ 102

C₄₆H₇₃N₃O₁₀ 103

C₄₆H₇₅N₃O₁₁ 104

C₄₇H₇₇NO₁₁ 105

C₄₆H₇₅NO₁₂ 106

C₄₇H₇₈N₂O₁₂ 107

C₄₇H₇₈N₂O₁₂ 108

C₄₇H₇₈N₂O₁₂ 109

C₄₅H₇₂N₂O₁₄ 110

C₅₀H₇₅N₃O₁₄ 111

C₄₃H₇₀N₂O₁₅S 112

C₄₆H₇₆N₂O₁₂ 113

C₅₀H₇₄Cl₂N₂O₁₂ 114

C₄₇H₇₈N₂O₁₂ 115

C₄₅H₇₄N₂O₁₂ 116

C₄₅H₇₄N₂O₁₂ 117

C₄₆H₇₆N₂O₁₂ 118

C₄₃H₇₁NO₁₂ 119

C₄₅H₇₂N₂O₁₂ 120

C₄₅H₇₂N₂O₁₂ 121

C₄₆H₇₄N₂O₁₂ 122

C₄₆H₇₄N₂O₁₂ 123

C₄₆H₇₄N₂O₁₂ 124

C₄₇H₇₆N₂O₁₂ 125

C₄₄H₇₀N₂O₁₁ 126

C₄₆H₇₅N₃O₁₁ 127

C₄₃H₆₇NO₁₄ 128

C₄₇H₇₆N₂O₁₃ 129

C₄₃H₆₉NO₁₁ 130

C₄₅H₇₃N₃O₁₁ 131

C₄₄H₆₇N₃O₁₁ 132

C₄₇H₇₇N₃O₁₁ 133

C₄₅H₇₀N₂O₁₁ 134

C₄₆H₇₄N₂O₁₃ 135

C₄₆H₇₄N₂O₁₃ 136

C₅₀H₇₃NO₁₃S 137

C₅₁H₇₃NO₁₃S 138

C₄₃H₆₉NO₁₁ 139

C₄₄H₆₉N₃O₁₂ 140

C₄₄H₆₉NO₁₁ 141

C₄₈H₈₀F₂NO₁₅P 142

C₄₆H₇₃FN₂O₁₂ 143

C₄₄H₆₅NO₁₂ 144

C₄₄H₇₀N₂O₁₁ 145

C₄₄H₇₀N₂O₁₁ 146

C₄₅H₇₁N₃O₁₂ 147

C₄₅H₇₁N₃O₁₂ 148

C₄₅H₇₁NO₁₂ 149

C₄₆H₇₄N₂O₁₂ 150

C₄₆H₇₄N₂O₁₂ 151

C₄₄H₆₈FNO₁₁ 152

C₄₆H₇₂N₂O₁₂ 153

C₄₆H₇₂N₂O₁₂ 154

C₄₇H₇₆N₂O₁₂ 155

C₄₇H₇₆N₂O₁₂ 156

C₂₁H₂₁N₇O₃ 157

C₄₃H₇₀N₂O₁₁ 158

C₄₃H₇₀N₂O₁₁ 159 160

C₄₄H₆₇NO₁₂ 161

C₄₅H₇₂N₂O₁₂ 162

C₄₃H₆₇NO₁₁ 163

C₄₅H₆₉NO₁₁ 164

C₄₆H₇₂N₂O₁₁ 165

C₄₉H₇₇NO₁₃ 166

C₅₀H₇₉NO₁₃ 167

C₄₃H₆₇NO₁₀ 168

C₄₄H₇₁NO₁₄ 169

C₄₄H₇₀ClNO₁₃ 170

C₅₂H₈₂N₂O₁₄ 171

C₅₀H₈₀N₂O₁₄ 172

C₄₃H₆₇NO₁₃ 173

C₄₄H₆₉NO₁₃ 174

C₄₆H₇₂N₂O₁₄ 175

C₄₈H₇₇N₃O₁₂ 176

C₅₁H₈₂N₂O₁₅ 177

C₅₁H₈₁N₃O₁₃ 178

C₄₆H₇₃N₃O₁₂ 179

C₄₇H₇₅N₃O₁₂ 180

C₄₆H₇₃NO₁₃ 181

C₄₅H₇₃NO₁₃ 182

C₄₆H₇₄N₂O₁₃ 183

C₄₆H₇₄N₂O₁₃ 184

C₄₇H₇₆N₂O₁₄ 185

C₅₂H₈₃N₃O₁₄ 186

C₈₆H₁₃₆N₂O₂₄ 187

C₄₃H₆₉NO₁₃ 188

C₄₅H₇₄N₂O₁₃ 189

C₄₅H₇₄N₂O₁₃ 190

C₄₈H₇₇NO₁₅ 191

C₅₁H₈₁N₃O₁₄ 192

C₅₂H₈₂N₂O₁₅ 193

C₆₃H₇₈N₂O₁₈ 194

C₅₀H₇₆N₆O₁₄ 195

C₅₆H₈₄N₄O₁₄ 196

C₅₆H₉₀N₄O₁₄ 197

C₅₁H₇₇N₅O₁₄ 198

C₅₃H₈₃N₃O₁₅ 199

C₄₉H₇₆N₂O₁₅ 200

C₄₈H₇₇N₃O₁₃ 201

C₄₉H₇₉N₃O₁₄ 202

C₄₉H₈₀N₂O₁₅ 203

C₅₅H₈₄N₄O₁₃ 204

C₄₅H₇₃NO₁₄ 205

C₄₃H₆₆N₂O₁₁ 206

C₄₃H₆₆N₂O₁₁ 207

C₄₃H₆₆N₂O₁₁ 208

C₅₁H₈₂N₂O₁₄ 209

C₅₁H₇₇N₃O₁₃ 210

C₅₁H₈₃N₃O₁₄ 211

C₅₀H₈₁N₃O₁₃ 212

C₄₈H₇₆N₂O₁₄ 213

C₅₂H₇₉N₃O₁₃ 214

C₄₉H₇₈N₂O₁₃ 215

C₄₆H₇₁N₃O₁₁ 216 217

C₄₅H₇₃N₃O₁₂ 218

C₄₈H₇₇N₃O₁₃ 219

C₄₄H₆₉NO₁₃

EXAMPLES Preparation of “C₂₂”-Oximes from FK506 or Ascomycin

Example Procedure: Combined FK506 (0.50 g, 0.60 mmol), hydroxylaminehydrochloride (0.50 g, 7.0 mmol), pyridine (0.25 mL, 3.2 mmol), andethanol (60 mL). The mixture was heated at reflux. LCMS at 2 h indicatedcomplete reaction. The mixture was cooled to rt, diluted with water, andtreated with dilute HCl (to˜pH4). The Ethanol was evaporated, and theresidue was extracted into DCM three times. The combined organic phasewas washed with brine, dried over Na₂SO₄, and evaporated to give a whitesolid. Purification by Biotage flash chromatography (25 g SNAP column,7-60% Acetone/Hexane). Fraction 16 (82 mg, 16%) appears to be enrichedin one oxime isomer, fraction 18 (68 mg, 13%) appears to be enriched inthe other oxime isomer, and fraction 17 (103 mg, 20%) is a less-enrichedmixture of isomers.

Preparation of “C22”-Hydrazones From FK506 or Ascomycin

Example Procedure: Combined FK506 (0.50 g, 0.62 mmol), Ethanol (35 mL),2-hydroxyethylhydrazine (0.25 mL, 3.7 mmol), and TsOH (0.71 g, 3.7 mmol). The mixture was stirred at rt for 20 h. The solvent was evaporated andthe residue was purified by Biotage flash chromatography (25 g SNAP,7-60% Acetone/Hexane). The appropriate fractions were combined andfurther purified by NP-HPLC (Kromasil, 4.6 mm×250 mm, 100-5 sil, 20%EtOH/Heptane). The appropriate fractions were combined and evaporated togive the desired material as a white solid (32 mg 6%).

Preparation of C23-C24-dehydro-C22-ethylhydrazone From FK506

Procedure: Combined FK506 (300 mg, 0.37 mmol), ethanol (21 mL),ethylhydrazine hydrochloride (216 mg, 2.2 mmol), and TsOH (426 mg, 2.2mmol), and the mixture was stirred at rt. LCMS at 18h indicated nostarting material remained. The mixture was diluted with DCM and waterand then adjusted to neutral pH with NaHCO₃. The organic solvents wereevaporated and the aqueous residue was extracted with DCM three times.The combined organics were washed with brine, dried over Na₂SO₄, andevaporated to give an oil. Purification with Biotage flashchromatography (25g SNAP, 7-60% acetone/hexanes). Both theC24-hydroxy-C22-hydrazone (24 mg, 8%) and theC23-C24-dehydro-C22-hydrazone (22 mg, 7%) were isolated from a separablemixture.

Preparation of C22 Exocyclic Alkenes from Ascomycin

Example Procedure using the Peterson Olefination:C24,C32-bis-TBS-protected ascomycin (0.18 g, 0.18 mmol) was dissolved inTHF (5 mL) and the solution was cooled to −78° C. TMSCH₂Li (0.44 mL of1M solution in pentane, 0.44 mmol) was added dropwise (a yellow colorappeared and dissipated with each drop, and then an orange color finallypersisted. The mixture was maintained at −78° C. for 20 h. The reactionwas quenched at −78° C. with two drops of glacial acetic acid. Water wasadded and the mixture was brought to rt. The mixture was treated with asaturated solution of NaHCO₃, and then the pH 8 mixture was extractedwith ether. The ethereal extract was washed with brine, dried overNa₂SO₄, and then evaporated to give an oil. This material was thendissolved in acetonitrile (4.5 mL), and treated with a 48% aqueous HFsolution (0.50 mL, 14 mmol). The mixture was stirred for 8 h, and thenquenched by the addition of ethoxytrimethylsilane (2.0 mL, 12.8 mmol).The mixture was evaporated to dryness and purified by Biotage flashchromatography (10 g SNAP column, 7-60% acetone/hexanes). The productcontaining fractions were combined and further purified by normal phaseHPLC (Kromasil, 4.6 mm×250 mm, 100-5 sil). The appropriate fractionswere combined to give the desired product as a glassy solid (9.2 mg,7%).

Example Procedure using a disubstituted alkyl lithium:C24,C32-bis-TBS-protected ascomycin (0.29 g, 0.28 mmol) was dissolved inTHF (8 mL) and the solution was cooled to −78° C. Sec-butyl lithium(0.50 mL of a 1.4 M solution in cyclohexane, 0.70 mmol) was addeddropwise (a yellow color appeared and dissipated with each drop, andthen an orange color finally persisted. The mixture was maintained at−78° C. for 24 h. The reaction was quenched at −78° C. with 3 drops ofglacial acetic acid. Water was added and the mixture was brought to rt.The mixture was treated with a saturated solution of NaHCO₃, and thenthe pH 8 mixture was extracted with ether. The ethereal extract waswashed with brine, dried over Na₂SO₄, and then evaporated to give anoily white solid. This material was then dissolved in acetonitrile (7.5mL), and treated with a 48% aqueous HF solution (0.80 mL, 22 mmol). Themixture was stirred for 8 h, and then quenched by the addition ofethoxytrimethylsilane (2.0 mL, 12.8 mmol). The mixture was evaporated todryness and purified by Biotage flash chromatography (10g SNAP column,7-60% acetone/hexanes). The product containing fraction was furtherpurified by normal phase HPLC (Kromasil, 4.6 mm×250 mm, 100-5 sil). Theappropriate fractions were combined to give the desired product (11 mg,5%).

Preparation of C22,C24-Acetonide From Ascomycin

Procedure: Dissolved Me₄N(OAc)₃BH (0.80 g, 0.30 mmol) in ACN (1 mL) andglacial acetic acid (1.5 mL) at rt. Cooled to 0° C. and stirred for 10min, then added a solution of ascomycin (0.30 g, 0.38 mmol) dissolved inACN (1.5 mL) and EtOAc (1 mL). The vial was sealed and the mixturestirred at 0° C. LCMS after 2 h indicated no starting material remained.The desired m/z was present along with the m/z corresponding toover-reduction. The reaction was quenched with Rochelle's Salt (0.5 M, 2mL) and the mixture was transferred to a round bottom flask andevaporated. The residue was extracted with ethyl acetate (3×25 mL). Thecombined organic phase was washed with brine, dried over sodium sulfate,and then the solvent was evaporated. The crude product was dissolved inacetone (13 mL) and 2,2-dimethoxypropane (13 mL), and then a catalyticamount of pyridiniump-toluenesulfonate was added (10 mg, 0.038 mmol).The mixture was stirred at rt, and after one day there was no remainingstarting material by TLC. The mixture was diluted with water, and thensaturated sodium bicarbonate solution was added (1 mL). The solventswere evaporated and the aqueous residue was extracted with DCM (3×25mL). The combined organic phase was washed with brine and dried oversodium sulfate. The solvent was evaporated to give a white solid whichwas purified by Biotage Isolera flash chromatography (10 g SNAP column,5-40-65% (ethyl acetate/hexanes) step-gradient. The appropriatefractions were combined to give the desired product as a white solid (19mg, 6%).

Preparation of C23-C24-dehydro-C22-methyloxime From Ascomycin

Procedure: Ascomycin (6.8 g, 8.6 mmol) was dissolved in toluene (140 mL)and then p-toluenesulfonic acid monohydrate (0.68 g, 3.6 mmol) was addedin one portion. The solution was heated to 80 ° C. The mixture continuedto stir at 80° C. for a total of 1 h. The mixture was cooled to rt, andwithout concentrating the solution, the mixture was passed through aplug of silica/Celite eluting with ether and toluene. A black insolubleresidue remained clinging to the flask. Concentration of the eluent invacuo provided a dark tar. The material was purified by Biotage flashchromatography in three portions (50 g SNAP, 7-40% acetone/hexanes). Theappropriate fractions from each chromatography were combined andevaporated to give Δ23-24-dehydroascomycin as a white powder (4.0 g,61%).

Δ23-24-dehydroascomycin (0.54 g, 0.70 mmol) was dissolved in absoluteethanol (65 mL), and then methoxylamine hydrochloride (0.70 g, 8.4 mmol)was added followed by pyridine (0.56 mL, 7.0 mmol). The mixture wasstirred at 60° C. After 3.5 h, the reaction was cooled to rt and dilutedwith water. The ethanol was rotary evaporated. The aqueous residue wastreated with a saturated aqueous NaHCO₃ solution to adjust to pH 6, andthen extracted with EtOAc (3×50 mL). The combined organic phase waswashed with brine, dried over Na₂SO₄, and evaporated to give a whitesolid. Purification by Biotage FC (25 g SNAP, 7-60% Acetone/Hexane). Theappropriate fractions were combined and evaporated to give the desiredproduct as a white solid (0.29 g, 51%).

Preparation of C24-deoxyascomycin

Ascomycin (6.8 g, 8.6 mmol) was dissolved in toluene (140 mL) and thenp-toluenesulfonic acid monohydrate (0.68 g, 3.6 mmol) was added in oneportion. The solution was heated to 80° C. The mixture continued to stirat 80° C. for a total of 1 h. The mixture was cooled to rt, and withoutconcentrating the solution, the mixture was passed through a plug ofsilica/Celite eluting with ether and toluene. A black insoluble residueremained clinging to the flask. Concentration of the eluent in vacuoprovided a dark tar. The material was purified by Biotage flashchromatography in three portions (50 g SNAP, 7-40% acetone/hexanes). Theappropriate fractions from each chromatography were combined andevaporated to give Δ73-24-dehydroascomycin as a white powder (4.0 g,61%).

The Δ23-24-dehydroascomycin (1.6 g, 2.0 mmol) was dissolved in methanol(25 mL) and added to a suspension of 10% palladium on carbon (0.12 g) inmethanol (25 mL). The flask was purged with nitrogen, then hydrogen. Aballoon with hydrogen was affixed to the flask with a needle through arubber septum. The mixture was stirred briskly for 18 min, beforecarefully filtering through a pad of Celite with MeOH (make sure to keepthe pad of Celite wet with MeOH). The solvent was evaporated to give agray foamy solid. Purification by Biotage flash chromatography (50gSNAP, 7-60% acetone/hexane, collecting on threshold (30 mAu). Fractions4-5 were combined and evaporated to give C24-deoxyascomycin as a foamywhite solid (0.73 g, 46%).

Preparation of C24-deoxy-C22-hydroxy Ascomycin

Ascomycin (6.8 g, 8.6 mmol) was dissolved in toluene (140 mL) and thenp-toluenesulfonic acid monohydrate (0.68 g, 3.6 mmol) was added in oneportion. The solution was heated to 80° C. The mixture continued to stirat 80° C. for a total of 1 h. The mixture was cooled to rt, and withoutconcentrating the solution, the mixture was passed through a plug ofsilica/Celite eluting with ether and toluene. A black insoluble residueremained clinging to the flask. Concentration of the eluent in vacuoprovided a dark tar. The material was purified by Biotage flashchromatography in three portions (50 g SNAP, 7-40% acetone/hexanes). Theappropriate fractions from each chromatography were combined andevaporated to give Δ73-24-dehydroascomycin as a white powder (4.0 g,61%).

The Δ23-24-dehydroascomycin (1.6 g, 2.0 mmol) was dissolved in methanol(25 mL) and added to a suspension of 10% palladium on carbon (0.12 g) inmethanol (25 mL). The flask was purged with nitrogen, then hydrogen. Aballoon with hydrogen was affixed to the flask with a needle through arubber septum. The mixture was stirred briskly for 18 min, beforecarefully filtering through a pad of Celite with MeOH (make sure to keepthe pad of Celite wet with MeOH). The solvent was evaporated to give agray foamy solid. Purification by Biotage flash chromatography (50 gSNAP, 7-60% acetone/hexane, collecting on threshold (30 mAu). Fractions4-5 were combined and evaporated to give C24-deoxyascomycin as a foamywhite solid (0.73 g, 46%).

To a solution of C24-deoxyascomycin (0.33 g, 0.42 mmol) in THF (4 mL) at−70° C. was added K-Selectride (1.1 mL of 1.0 M soln in THF, 1.1 mmol)dropwise. The temperature remained at −70° C. to −40° C., and TLC at 4 hindicated no rxn. The clear/colorless soln was placed into the −20° C.freezer. It gradually turned yellow, then orange, over a 2 h period. Themixture was cautiously poured into a beaker of ice. Dilute HCl was addedto adjust to neutral pH (the solution became colorless). The mixture wasextracted with ethyl acetate (3×50 mL). The combined organic phase wassuccessively washed with water and brine, then dried over Na₂SO₄. Thevolatiles were evaporated to give a yellow oil. The mixture was purifiedby Biotage FC (25 g SNAP, 7-60% Acetone/Hexanes). The appropriatefractions were combined and evaporated to give the desired product as awhite solid (0.16 g, 48%).

Preparation of C22-oximes-C21-alkenes (other than allyl) From Tacrolimus

Example Procedure using hydroxylamine and propene: FK506 (2.0 g, 2.5mmol) was dissolved in diethyl ether (40 mL), and the mixture wasde-gassed with nitrogen for 10 min.Dichloro[1,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II) “Furstner catalyst” (30 mg) andCuI (20 mg) were then added, followed by liquid propene (5 mL, condensedfrom gas) and the mixture was stirred for 16 h at rt. Isolute Si-Thiolresin (Biotage) was added, and the mixture was stirred for 1 hr, thenallowed to stand. The supernatant was decanted, and the resin was washedwith ether (20 mL) and hexane (20 mL). The combined supernatants wereconcentrated in vacuo to an oily residue. This material was purified bypreparative HPLC to give the desired propenyl compound as a white solid.

The product from above (0.10 g, 0.12 mmol), hydroxylamine hydrochloride(0.017 g, 0.24 mmol), pyridine (1 mL), and ethanol (1 mL) were placed ina 4 mL vial and stirred overnight at rt. The ethanol was evaporated andthe residue was poured into 1M HCl (aq). The product was extracted withdichloromethane, and the solvent was evaporated to give a clear glassysolid. This material was purified by Biotage flash chromatography (10 gSNAP, 40% acetone/hexane). The appropriate fractions were collected,pooled and concentrated to give a glassy solid which was then dissolvedin acetonitrile/water and lyophilized to give the desired product (apair of isomers) as a white powder (10 mg, 10%).

Activity: Activity against C. neo, Candida, Candida w/ FLu., Asp, andAsp/Caspo was determined using standardized in vitro susceptibilitytests; see, Clinical and Laboratory Standards Institute (CLSI) and theEuropean Committee for Antimicrobial Susceptibility Testing (EUCAST),and compounds 2-219 each demonstrate antifungal activity against one ormore of these fungi; exemplary, excerpted data are shown below.

Active Active Candida Active Asp Active Asp Compound C. neo w/ FLu.alone (MEC) Caspo 2 yes no yes Yes 3 yes yes no yes 4 ug/mL 4 yes yes noyes 8 ug/mL 5 yes yes yes yes (8 ug/mL) 1 ug/mL

Compounds most active against C. neo include #2-6, 8, 11, 14-18, 20,23-24, 26-28, 30-32, 35-44, 47, 50, 55, 58-80, 82, 86-91, 97-102, 116,118-120, 123, 127-128, 133-135, 138-150 and 152-161.

Compounds most active against Asp include #2, 5, 11, 15-18, 23, 24, 26,39, 52, 55, 79, 86, 87, 89, 97-101, 132-141, 144, 146-150, 152, 153,155-158, 160, 161, 163, 166, 174, 178, and 179-181.

IL2 IC₅₀ values were also determined, with compounds 2-219 demonstratingIC₅₀ in the subnanomolar (e.g. # 42, 51, 61, 75-76, 103, 126, 129, 132,138, 140, 151, 163), nanomolar (e.g. #2, 3, 8, 18, 23-24, 31-32, 37,39-40, 44, 52, 60, 62- 66, 68-69, 71-72, 77- 79, 81-91, 96-102, 104-125,127, 130-131, 133-137, 139, 142-150, 152-154, 157-158, 160-162, 164-168,170, 172-175, 178-179, 184) and micromolar (e.g. #53, 55-57, 67, 70,73-74, 80, 112, 155, 177) ranges.

The invention encompasses all combinations of recited particular andpreferred embodiments. It is understood that the examples andembodiments described herein are for illustrative purposes only and thatvarious modifications or changes in light thereof will be suggested topersons skilled in the art and are to be included within the spirit andpurview of this application and scope of the appended claims. Allpublications, patents, and patent applications cited herein, includingcitations therein, are hereby incorporated by reference in theirentirety for all purposes.

1. (canceled)
 2. A composition comprising a compound of formula (I):

wherein: “a” is a double bond that may be present provided that R^(5a)is not present; R¹ is selected from alkyl, alkenyl; R³ and R^(3a) areindependently selected from —H, and —OH, or R³ and R^(3a) together form═X, where X is selected from O, C, and N such that ═X and the carbonatom to which it is attached forms a carbonyl, oxime, substituted oxime,imine, substituted imine, hydrazone, substituted hydrazone, terminalolefin, or substituted olefin functional group; R⁵ is —OH and R^(5a) is—H; R⁷ is —OH and R^(7a) is —H; and R9 is —H, or a pharmaceuticallyacceptable salt thereof.
 3. The composition of claim 2, wherein R1 isalkenyl.
 4. The composition of claim 2, wherein R³ and R^(3a) togetherform ═X, where X is selected from O, C, and N such that ═X and thecarbon atom to which it is attached forms a carbonyl, oxime, substitutedoxime, imine, substituted imine, hydrazone, substituted hydrazone,terminal olefin, or substituted olefin functional group.
 5. Thecomposition of claim 4, wherein R³ and R^(3a) together form an imine, asubstituted imine, a hydrazone, or a substituted hydrazine.
 6. Thecomposition of claim 2, wherein the compound is